title: Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver.
abstract: The mammalian liver regenerates upon tissue loss, which induces quiescent hepatocytes to enter the cell cycle and undergo limited replication under the control of multiple hormones, growth factors, and cytokines. Endocannabinoids acting via cannabinoid type 1 receptors (CB(1)R) promote neural progenitor cell proliferation, and in the liver they promote lipogenesis. These findings suggest the involvement of CB(1)R in the control of liver regeneration. Here we report that mice lacking CB(1)R globally or in hepatocytes only and wild-type mice treated with a CB(1)R antagonist have a delayed proliferative response to two-thirds partial hepatectomy (PHX). In wild-type mice, PHX leads to increased hepatic expression of CB(1)R and hyperactivation of the biosynthesis of the endocannabinoid anandamide in the liver via an in vivo pathway involving conjugation of arachidonic acid and ethanolamine by fatty-acid amide hydrolase. In wild-type but not CB(1)R(-/-) mice, PHX induces robust up-regulation of key cell-cycle proteins involved in mitotic progression, including cyclin-dependent kinase 1 (Cdk1), cyclin B2, and their transcriptional regulator forkhead box protein M1 (FoxM1), as revealed by ultrahigh-throughput RNA sequencing and pathway analysis and confirmed by real-time PCR and Western blot analyses. Treatment of wild-type mice with anandamide induces similar changes mediated via activation of the PI3K/Akt pathway. We conclude that activation of hepatic CB(1)R by newly synthesized anandamide promotes liver regeneration by controlling the expression of cell-cycle regulators that drive M phase progression.
authors.affiliation: Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bani
authors.initials: B
authors.lastname: Mukhopadhyay
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.forename: Shi
authors.initials: S
authors.lastname: Yin
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Joseph
authors.initials: J
authors.lastname: Tam
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Godlewski
authors.forename: Judith
authors.initials: J
authors.lastname: Harvey-White
authors.forename: Isioma
authors.initials: I
authors.lastname: Mordi
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Sophie
authors.initials: S
authors.lastname: Lotersztajn
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Qiaoping
authors.initials: Q
authors.lastname: Yuan
authors.forename: Kornel
authors.initials: K
authors.lastname: Schuebel
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: George
authors.initials: G
authors.lastname: Kunos
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis*; D002453:Cell Cycle; D063388:Endocannabinoids; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C078814:anandamide